Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by motor impairments and loss of dopaminergic neurons in the substantia nigra. FLZ (formulated as: N-2-(4-hydroxy-phenyl)-ethyl]-2-(2, 5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic derivative of squamosamide from a Chinese herb and has been proven to protect dopaminergic neurons in subacute PD models. However, whether FLZ has a neuroprotective effect on chronic PD model is still unknown. The present study was designed to verify the neuroprotection of FLZ on chronic PD mouse model induced by MPTP combined with probenecid (MPTP/p). The results showed that treatment of mice with FLZ for 9 weeks significantly improved motor behavior and dopaminergic neuronal function of mice injected with MPTP/p. The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level, and tyrosine hydroxylase (TH) activity, as well as decrease of α-synuclein (α-Syn) expression, α-Syn phosphorylation, nitration, and aggregation. Moreover, FLZ decreased the interaction between α-Syn and TH, which eventually improved dopaminergic neuronal function. Mechanistic study demonstrated that FLZ increased Akt and mTOR phosphorylation, suggesting that FLZ activated Akt/mTOR signaling pathway and this might be involved in the neuroprotection of FLZ. The present results provided more elaborate in vivo evidences to support the neuroprotective effect of FLZ on dopaminergic neurons of chronic PD mouse model and the potential of FLZ to be developed as new drug to treat PD.